Polymorphic forms of Cyclo (-His-Pro) and methods of use to treat kidney disease
Inventors
Olmstead, Kay • Pearson, David • McPherson, Elaine
Assignees
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Publication Number
US-11820834-B2
Publication Date
2023-11-21
Expiration Date
Abstract
The present disclosure relates to synthesis and characterization of novel polymorphic forms of Cyclo (-His-Pro) (“CHP”).
Core Innovation
Cyclo(-His-Pro) hydrate (CHP hydrate) is disclosed as a solid form, including distinguishing pattern 2 hydrate from pattern 1 anhydrous form and characterizing their respective solid-state behavior. The work focuses on producing and identifying a specific stoichiometric mono-hydrate corresponding to pattern 2, supported by analytical characterization and polymorph screening results.
The characterization relies on XRPD, PLM, TG/DTA, DSC, DVS/VT-DVS, VT-/VH-XRPD, NMR, and HPLC/chiral HPLC. The document reports solid-state transitions including dehydration and re-crystallization behavior, purity and chiral purity, and stability comparisons showing improved stability of pattern 2 hydrate under accelerated conditions versus anhydrate pattern 1, with form conversion trends dependent on humidity and temperature.
Pharmaceutical compositions comprise cyclo(-His-Pro) hydrate pattern 2 as an active ingredient, including embodiments with pharmaceutically acceptable carriers/excipients and multiple administration routes. The document further describes treatment use statements directed to kidney disease, including acute kidney injury (AKI), chronic kidney disease (CKD), and kidney fibrosis.
Claims Coverage
The provided independent claim set includes one independent claim directed to a treatment method for kidney disease, with the cyclo(-His-Pro) hydrate active ingredient characterized by a specific XRPD diffractogram peak set. The claim coverage centers on the defined structural identification of the active ingredient, and dependent claims further add physicochemical constraints, a minimum purity requirement, a kidney disease category refinement, and optional zinc-related formulation components.
Xrpd-characterized cyclo(-His-Pro) hydrate for kidney treatment
A method comprising administering an effective amount of a composition having a cyclo(-His-Pro) hydrate active ingredient, where the cyclo(-His-Pro) hydrate compound is characterized by an XRPD diffractogram comprising peaks at 2θ values 13.7°±0.2°, 17°±0.2°, and 27.3°±0.2°.
Kidney disease treatment indication limited to AKI, CKD, or kidney fibrosis
The method is for treating kidney disease selected from acute kidney injury (AKI), chronic kidney disease (CKD), or kidney fibrosis.
Additional xrpd peak constraint
The cyclo(-His-Pro) hydrate compound has an XRPD diffractrogram including a peak at a 2θ value of 10°±0.2°.
Dsc endotherm onset temperature range constraint
The cyclo(-His-Pro) hydrate compound has a differential scanning calorimetry (DSC) endotherm onset temperature between about 75°C and about 100°C.
Minimum purity requirement for the cyclo(-His-Pro) hydrate
Using the cyclo(-His-Pro) hydrate compound having a purity of at least 90%.
Zinc-form metal/metal compound selection
The metal or metal compound is selected from zinc element, zinc cation, zinc gluconate, zinc acetate, zinc sulfate, zinc picolinate, zinc orotate, or zinc citrate.
Overall, the claim set ties kidney-disease treatment to a composition containing a cyclo(-His-Pro) hydrate active ingredient defined by a specified XRPD peak set, and it tightens the active ingredient definition using additional XRPD peak constraints, DSC endotherm onset temperature range, and a minimum purity threshold. The claim set also narrows the therapeutic indication to AKI, CKD, or kidney fibrosis and includes dependent formulation selection aspects for zinc forms.
Stated Advantages
Pattern 2 is reported to have superior stability over Pattern 1.
Pattern 2 is described as resisting humidity-driven conversion to Pattern 1 under specified conditions.
Some conversion to Pattern 1 is reported at higher temperature and low relative humidity.
Improved stability of pattern 2 hydrate under accelerated conditions versus anhydrate pattern 1.
Documented Applications
Treatment use statements for kidney disease, including acute kidney injury (AKI), chronic kidney disease (CKD), and kidney fibrosis.
Pharmaceutical composition embodiments comprising cyclo(-His-Pro) hydrate pattern 2 as an active ingredient with multiple administration routes and pharmaceutically acceptable carriers/excipients.
Treating kidney disease in a subject in need thereof using a composition comprising a cyclo(-His-Pro) hydrate active ingredient characterized by specified XRPD diffractogram peaks.
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